Abstract
Secretion of adrenomedullin (ADM) is stimulated by volume overload to maintain endothelial barrier function, and higher levels of biologically active (bio-) ADM in heart failure (HF) are a counteracting response to vascular leakage and tissue oedema. This study aimed to establish the value of plasma bio-ADM as a marker of congestion in patients with worsening HF. The association of plasma bio-ADM with clinical markers of congestion, as well as its prognostic value was studied in 2179 patients with new-onset or worsening HF enrolled in BIOSTAT-CHF. Data were validated in a separate cohort of 1703 patients. Patients with higher plasma bio-ADM levels were older, had more severe HF and more signs and symptoms of congestion (all P < 0.001). Amongst 20 biomarkers, bio-ADM was the strongest predictor of a clinical congestion score (r2 = 0.198). In multivariable regression analysis, higher bio-ADM was associated with higher body mass index, more oedema, and higher fibroblast growth factor 23. In hierarchical cluster analysis, bio-ADM clustered with oedema, orthopnoea, rales, hepatomegaly and jugular venous pressure. Higher bio-ADM was independently associated with impaired up-titration of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers after 3 months, but not of beta-blockers. Higher bio-ADM levels were independently associated with an increased risk of all-cause mortality and HF hospitalization (hazard ratio 1.16, 95% confidence interval 1.06-1.27, P = 0.002, per log increase). Analyses in the validation cohort yielded comparable findings. Plasma bio-ADM in patients with new-onset and worsening HF is associated with more severe HF and more oedema, orthopnoea, hepatomegaly and jugular venous pressure. We therefore postulate bio-ADM as a congestion marker, which might become useful to guide decongestive therapy.
Highlights
Secretion of adrenomedullin (ADM) is stimulated by volume overload to maintain endothelial barrier function, and higher levels of biologically active ADM in heart failure are a counteracting response to vascular leakage and tissue oedema
The most dominant role of ADM is thought to be the regulation of endothelial function, and ADM has been shown to play an essential role in maintaining endothelial barrier function and disruption hereof results in vascular leakage, and systemic and pulmonary edema.[9, 10] ADM expression is stimulated by volume overload and increased plasma ADM reflects excessive fluid overload.[11]. In a recent study in patients with acute heart failure, biologically active adrenomedullin (bio-ADM) at baseline was associated with more signs of congestion and higher bio-ADM levels after 7 days of decongestive treatment were associated with significant residual congestion at this time point.[7]. The findings from this study suggest that bio-ADM might be a potential marker of congestion both at admission and during/after a hospitalization for acute heart failure
During the first three months after enrollment, investigators were expected to optimize treatment of heart failure with angiotensin converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) and beta-blockers, according to the doses indicated in the 2008 European Society of Cardiology Guidelines.[12]. The results were subsequently validated in the BIOSTAT-CHF validation cohort, in which 1,738 patients were recruited from six centers in Scotland, United Kingdom
Summary
Secretion of adrenomedullin (ADM) is stimulated by volume overload to maintain endothelial barrier function, and higher levels of biologically active (bio-) ADM in heart failure are a counteracting response to vascular leakage and tissue oedema. The most dominant role of ADM is thought to be the regulation of endothelial function, and ADM has been shown to play an essential role in maintaining endothelial barrier function and disruption hereof results in vascular leakage, and systemic and pulmonary edema.[9, 10] ADM expression is stimulated by volume overload and increased plasma ADM reflects excessive fluid overload.[11] In a recent study in patients with acute heart failure, bio-ADM at baseline was associated with more signs of congestion and higher bio-ADM levels after 7 days of decongestive treatment were associated with significant residual congestion at this time point.[7] The findings from this study suggest that bio-ADM might be a potential marker of congestion both at admission and during/after a hospitalization for acute heart failure. We aimed to further evaluate clinical and biological factors associated with bio-ADM in patients with worsening and new-onset heart failure, and assess associations with congestion and outcome, in order to gain greater insight in the potential role of bio-ADM in heart failure
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